Corticotropin-releasing factor (CRF) and CRF-related neuropeptides have an important role in the central nervous system mediating behavioral responses to stressors. CRF antagonists are very effective in reversing stress-induced suppression and activation in behavior. Brain sites implicated in the behavioral effects of CRF include the locus coeruleus, paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminals, and the central nucleus of the amygdala. The present series of proposed studies is to further explore the role of CRF related neuropeptides in activation, behavioral responses to stressors and feeding. An additional CRF-like neuropeptide, urocortin, has been identified in the brain and has a high affinity for the CRF-2 receptor in addition to the CRF-1 receptor. Urocortin has many of the effects of CRF but also is significantly more potent and effective than CRF in decreasing feeding in both meal-deprived and free-feeding rats. In Specific Aim 1, the brain sites that are most sensitive to the effects of CRF will be compared to the brain sties most sensitive to the effects of urocortin using intracranial microinjection of CRF related neuropeptides. The neuropharmacological mechanisms involved in mediating the activation, stress-enhancing and suppression of feeding produced by CRF and urocortin will be explored in Specific Aim 2. In mouse genetic models, mice over-expressing CRF show anxiogenic-like responses compared to wild-type mice, and mice lacking the CRF-1 receptor showed a behavioral profile of decreased behavioral responses to stressors, compared to wild-type mice. Results to date have led to the hypothesis that CRF-1 receptors may mediate CRF- like neuropeptide effects on activation and behavioral responses to stressors, but CRF-2 receptors may mediate the suppression of feeding produced by CRF-like neuropeptides. This hypothesis will be further explored in Specific Aim 3 where systematic assessment of the effects of CRF and urocortin on activation, behavioral responses to stressors and feeding will be explored in CRF-1, CRF-2 and CRF-1/CRF-2 knockout mice. Finally in Specific Aim 3 where systematic assessment of the effects of CRF and urocortin on activation, behavioral responses to stressors and feeding will be explored in CRF-1, CRF-2 and CRF-1/CRF- 2 knockout mice. Finally in Specific Aim 4, novel ligands and/or CRF receptors under the auspices of the Program Project will be assessed using sensitive behavioral tests of activation, behavioral tests of activation, behavioral responses to str5essors and feeding in rats and mice. Results of the present series of studies will provide key information regarding the role of CRF related neuropeptides in central nervous system function and may provide insights into the possible role of CRF in a variety of stress related psychopathology.